Download Product Information: Mycophenolate sodium

Attachment 1: Product information for AusPAR Myfortic Mycophenolate sodium Novartis Australia
Pty Limited PM-2010-01235-3-2 Date of Finalisation 17 May 2013. This Product Information was
approved at the time this AusPAR was published.
1
MYFORTIC®
(mycophenolic acid as sodium salt)
NAME OF THE MEDICINE
Active ingredient: Mycophenolic acid (as sodium salt)
Chemical Name: (E)-6-(4- Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5yl)-4-methyl-hex-4-enoic acid sodium salt
Empirical formula: C17H19O6Na
Molecular weight: 342.32
Structural formula:
O
O
O
OH
O
OH
as the sodium salt
CAS Registry Number: 37415-62-6
DESCRIPTION
Mycophenolate sodium is the sodium salt of the active moiety, mycophenolic acid, and is a
white to off-white, fine crystalline powder. It is freely soluble in aqueous media at
physiological pH, as in the upper intestine, but practically insoluble in 0.1M HCl.
Each enteric-coated tablet contains 180 mg or 360 mg of mycophenolic acid (as the sodium
salt), equivalent to 192.4 and 384.4 mycophenolate sodium.
Excipients: Starch-maize, povidone, crospovidone, lactose, silica-colloidal anhydrous,
magnesium stearate. The enteric coating consists of: hypromellose phthalate, titanium
dioxide, iron oxide yellow CI77492, indigo carmine CI73015 (180 mg tablet), iron oxide red
CI77491 (360 mg tablet).
PHARMACOLOGY
Pharmacodynamics
Mycophenolic acid (MPA) is a non-nucleoside, non-competitive, reversible inhibitor of
inosine monophosphate dehydrogenase (IMPDH). IMPDH is the rate limiting enzyme in the
de novo synthesis pathway of guanosine triphosphate. Both T- and B-lymphocytes are highly
dependent on this pathway for the generation of guanosine nucleotides whereas non-lymphoid
cells can utilise a salvage pathway for the generation of guanosine triphosphate. MPA
selectively decreases the lymphocyte nucleotide pool, which effectively impairs the capacity
Attachment 1: Product information for AusPAR Myfortic Mycophenolate sodium Novartis Australia
Pty Limited PM-2010-01235-3-2 Date of Finalisation 17 May 2013. This Product Information was
approved at the time this AusPAR was published.
2
of T- and B-lymphocytes to proliferate. MPA inhibits glycosylation of adhesion molecules on
lymphocytes and monocytes (a process requiring guanosine triphosphate). This action could
potentially decrease the recruitment of lymphocytes and monocytes into sites of chronic
inflammation, an important process in ongoing rejection.
PHARMACOKINETICS
Absorption:
Following oral administration, mycophenolate sodium is extensively absorbed. The median
time to maximum MPA plasma concentration (tmax) is 2 hours (Table 1) but there is
significant variability, especially with food, with values up to 16 hours fasting and 24 hours
fed. In vitro studies demonstrated that the enteric-coated formulation of Myfortic prevents
the release of MPA under acidic condition, as in the stomach.
In stable renal transplant patients on cyclosporin (Neoral®) based immunosuppression, the
mean absolute bioavailability of Myfortic tablets was 71% (range: 38-98%). Myfortic
pharmacokinetics are dose proportional and linear over the studied dose range of 180 to
2160 mg. Compared to the fasting state, administration of Myfortic 720 mg with a high fat
meal had no effect on the systemic exposure (AUC) of MPA, which is the most relevant
pharmacokinetic parameter linked to efficacy. However, there was a 33% decrease in the
maximal plasma concentration (Cmax) of MPA and a delay in tmax when Myfortic was given
with a high fat meal.
Distribution:
The volume of distribution at steady state for MPA is 50 litres. Both MPA and its major
metabolite, mycophenolic acid glucuronide (MPAG), are highly protein bound, 97% and
82%, respectively. The free MPA concentration may increase under conditions of decreased
protein binding sites (uraemia, hepatic failure, hypoalbuminaemia, concomitant use of drugs
with high protein binding) and this may put patients at increased risk of MPA-related adverse
effects.
Metabolism:
The half life of MPA (mean + SD) is 11.7 + 3.2 hours and the clearance (mean + SD) is 8.4 +
1.8 L/hr. MPA is metabolised principally by glucuronyl transferase to form the phenolic
glucuronide of MPA, mycophenolic acid glucuronide. MPAG is the predominant metabolite
of MPA and is pharmacologically inactive. In stable renal transplant patients on Neoral based
immunosuppression, approximately 28% of the oral Myfortic dose is converted to MPAG by
presystemic metabolism. The half-life of MPAG (mean + SD) is approximately 15.7 + 3.9
hours and its clearance (CL/fm) is about 0.45 + 0.15 L/hr (mean + SD).
Attachment 1: Product information for AusPAR Myfortic Mycophenolate sodium Novartis Australia
Pty Limited PM-2010-01235-3-2 Date of Finalisation 17 May 2013. This Product Information was
approved at the time this AusPAR was published.
3
Excretion:
Although negligible amounts of MPA are present in the urine (<1%), the majority of MPA is
eliminated in the urine as MPAG. MPAG secreted in the bile is available for deconjugation
by gut flora. The MPA resulting from this deconjugation may then be reabsorbed.
Approximately 6-8 hours after Myfortic dosing, a second peak of MPA concentration can be
measured, consistent with reabsorption of the deconjugated MPA.
Pharmacokinetics in renal transplant patients on cyclosporin based
immunosuppression:
Table 1 shows the mean pharmacokinetic parameters for MPA following administration of
Myfortic. In the early post transplant period, mean MPA AUC and mean MPA Cmax were
approximately one-half of that measured six months post transplant.
Table 1: Mean (SD) pharmacokinetic parameters for MPA following oral
administration of Myfortic to renal transplant patients on Neoral based
immunosuppression
Adult
single dose
Adult
multiple dose
x 6 days, BID
n=12
n = 24
Adult
multiple dose
x 28 days, BID
n=36
Adult
chronic, multiple dosing
BID
n=48
Dose (oral)
720 mg
720 mg
720 mg
Post Transplant
14 days
3
6
months
months
720 mg
720 mg 720 mg
Tmax
(median)
Cmax (ug/mL)
2 hrs
2 hrs
2.5 hrs
2 hrs
2 hrs
2 hrs
26.1 (12.0)
37.0 (13.3)
31.2 (18.1)
13.9 (8.6)
AUC o-
(ug*hr/mL)
AUC o-12
(ug*hr/mL)
66.5 (22.6)
-
-
-
24.6
(13.2)
-
23.0
(10.1)
-
-
67.9 (20.3)
71.2 (26.3)
29.1 (10.4)
50.7
(17.3)
55.7
(14.6)
Pharmacokinetics in special patient groups:
Gender: There are no clinically significant gender differences in Myfortic pharmacokinetics.
Elderly: Pharmacokinetics in the elderly have not been formally studied. The exposure of
MPA does not appear to vary to a clinically significant degree by age.
Impaired renal function: There are no data for Myfortic. After a single dose of
mycophenolate mofetil containing an equivalent amount of MPA to 720 mg of Myfortic,
clearance of MPA appeared to be reduced with increasing levels of renal impairment. The
area under the MPA plasma concentration – time curve (MPA exposure) increased by up to
30% in patients with mild to moderate renal impairment (GFR 25-80 mL/min/1.73m2) and
75% in patients with severe renal impairment (GFR < 25 mL/min/1.73m2). However, there
Attachment 1: Product information for AusPAR Myfortic Mycophenolate sodium Novartis Australia
Pty Limited PM-2010-01235-3-2 Date of Finalisation 17 May 2013. This Product Information was
approved at the time this AusPAR was published.
4
was considerable variability and small numbers of subjects (6-7 at each level of renal
impairment). MPAG exposure was 3 to 6-fold higher in subjects with moderate to severe
renal impairment, which was consistent with renal elimination of MPAG.
At higher MPAG concentrations (observed in patients with renal impairment or delayed graft
function), plasma protein binding of MPA may be reduced as a result of competition between
MPAG and MPA for binding sites. This would result in increased free MPA in plasma.
Impaired hepatic function: There are no data for Myfortic. After a single dose of
mycophenolate mofetil equivalent to 720 mg MPA in patients with alcoholic cirrhosis,
hepatic MPA glucuronidation processes were relatively unaffected by hepatic parenchymal
disease. Effects of hepatic disease on this process probably depend on the particular disease.
However, hepatic disease with predominantly biliary damage, such as primary biliary
cirrhosis, may show a different effect.
CLINICAL TRIALS
Renal transplant
Two multi-centre, randomised, double-blind, parallel group studies were conducted in renal
transplant patients. The first study was conducted in newly transplanted patients and in the
second study, maintenance renal transplant patients were randomised 1:1 to either remain on
mycophenolate mofetil (MMF) or be switched to Myfortic. Both pivotal studies were
reference therapy-controlled clinical studies using commercially marketed MMF as the
comparator.
De novo Renal Transplant Patients
A total of 423 patients were randomised within 48 hours of renal transplantation, 213 to
Myfortic (1.44 g/ day, 720 mg bid) and 210 to MMF (2 g/day, 1 g bid) as part of triple
immunosuppressive therapy with Neoral and steroids. The aim of the study was to show
therapeutic equivalence of Myfortic to MMF as measured by the incidence of biopsy-proven
acute rejection, graft loss, death or lost to follow-up at 6 and 12 months of treatment. All
patients contributed data at 6 and 12 months. Efficacy results are reported in Table 2 for the
intent-to-treat population. Similar results were obtained for the per protocol analysis – an
analysis which excluded patients with serious protocol violations.
Attachment 1: Product information for AusPAR Myfortic Mycophenolate sodium Novartis Australia
Pty Limited PM-2010-01235-3-2 Date of Finalisation 17 May 2013. This Product Information was
approved at the time this AusPAR was published.
5
Table 2: Analysis of primary efficacy endpoint and its components at 6 and 12 months
(Study ERL B301)
6 months
Biopsy-proven acute rejection episode,
graft loss, death or lost to follow-up
Biopsy proven acute rejection episode
Graft loss or death
Graft loss
Death
Lost to follow-up*
12 months
Biopsy-proven acute rejection episode,
graft loss, death or lost to follow-up
Biopsy proven acute rejection episode
Graft loss or death
Graft loss
Death
Lost to follow-up*
Myfortic
1.44 g/day
(n = 213)
n (%)
55 (25.8)
MMF
2 g/day
(n = 210)
n (%)
55 (26.2)
95% CI
ERL-MMF
46 (21.6)
8 (3.8)
7 (3.3)
1 (0.5)
3 (1.4)
48 (22.9)
11 (5.2)
9 (4.3)
2 (1.0)
0
(-9.2, 6.7)
(-5.4, 2.5)
(-4.6, 2.6)
60 (28.2)
59 ( 28.1)
(-8.5, 8.6)
48 (22.5)
10 (4.7)
8 (3.8)
2 (0.9)
5 (2.3)
51 (24.3)
14 (6.7)
9 (4.3)
5 (2.4)
0
(-9.8, 6.3)
(-6.4, 2.4)
(-4.3, 3.2)
(-8.7, 8.0)
* Lost to follow-up indicates patients that were lost to follow-up without prior biopsy-proven acute rejection,
graft loss or death.
The criteria for therapeutic equivalence were met: the 95% CI for the difference in incidence of the primary
variable (Biopsy-proven acute rejection episode, graft loss, death or lost to follow-up at Month 6) was entirely
contained in the interval (-12%, 12%).
Maintenance Renal Transplant Patients
A total of 322 patients who were at least 6 months post-renal transplant and stabilised on 2 g
MMF and Neoral, were randomised, 159 to Myfortic (1.44 g/ day, 720 mg bid) and 163 to
MMF (2 g/day, 1 g bid) plus Neoral, with or without steroids. The primary objective was to
demonstrate safety and tolerability of Myfortic compared to MMF and this objective was met.
Evaluation of efficacy was a secondary objective. The incidence rate of biopsy-proven acute
rejection, graft loss, death or lost to follow-up, and the incidence of suspected or biopsyproven acute rejections within 6 and 12 months post-randomisation, were compared across
treatment groups. All patients contributed data at 6 months, and 223 patients contributed data
at 12 months. Efficacy results are shown in Table 3.
Attachment 1: Product information for AusPAR Myfortic Mycophenolate sodium Novartis Australia
Pty Limited PM-2010-01235-3-2 Date of Finalisation 17 May 2013. This Product Information was
approved at the time this AusPAR was published.
6
Table 3: Secondary efficacy endpoints (Study ERL B302)
6 months
Biopsy-proven acute rejection episode,
graft loss, death or lost to follow-up
Biopsy-proven acute rejection episode,
biopsy-proven chronic rejection, graft
loss, death or lost to follow-up
Acute rejection
Biopsy-proven acute rejection
Biopsy-proven chronic rejection
Lost to follow-up*
Graft loss or death
12 months
Biopsy-proven acute rejection episode,
graft loss, death or lost to follow-up
Biopsy-proven acute rejection episode,
biopsy-proven chronic rejection, graft
loss, death or lost to follow-up
Lost to follow up*
Graft loss or death
Myfortic
1.44 g/day
(n = 159)
n (%)
6 (3.8)
MMF
2 g/day
(n = 163)
n (%)
10 (6.1)
(95% CI)
Myfortic-MMF
9 (5.7)
11 (6.7)
(-6.4, 4.2)
2 (1.3)
2 (1.3)
4 (2.5)
4 ( 2.5)
0
n (%)
n =110
10 (9.1)
3 (1.8)
2 (1.2)
4 (2.5)
6 (3.7)
2 (1.2)
n (%)
n = 113
14 (12.4)
(-10.9, 5.5)
-
13 (11.8)
15 (13.3)
-
7 (6.4)
1 (0.9)
8 (7.1)
4 (3.5)
(-7.1, 2.4)
-
* Lost to follow-up indicates patients that were lost to follow-up without prior biopsy-proven acute rejection,
graft loss or death.
Lupus nephritis
One exploratory randomised open-label 6-month study (A2420; Zeher et al., 2011) has been
conducted comparing the efficacy and safety of Myfortic and a standard corticosteroid
regimen (prednisolone 1 mg/kg bodyweight/day, tapered) with Myfortic and a reduced
corticosteroid regimen (prednisolone 0.5 mg/kg bodyweight/day, tapered) for induction
treatment of lupus nephritis. Male and female patients aged ≥ 18 years were eligible to enter
the study if they met the following criteria: diagnosed with SLE, defined as meeting at least
four classification criteria of the American College of Rheumatology; presence of
proliferative lupus nephritis flare class III or IV (ISN/RPS classification of lupus nephritis)
documented by a renal biopsy performed within 24 months preceding the study entry;
proteinuria defined as >0.5 gram urine protein per gram urine creatinine at screening and
baseline and clinical activity defined by serum creatinine >1.0 mg/dL (88.4 μmol/L),
microscopic hematuria (>5 red cells per high power field) or presence of cellular casts were
the other key inclusion criteria. The key exclusion criteria were patients with calculated
creatinine clearance <30 mL/min (using the Cockcroft-Gault formula); patients having
received i.v. CS bolus, oral or i.v. cyclophosphamide or MMF during the last 3 months; use
of any antibodies during the last 6 months. Myfortic was administered at a dose of 720 mg
twice daily for 2 weeks and then 1080 mg twice daily (or 720 mg three times daily) for 22
Attachment 1: Product information for AusPAR Myfortic Mycophenolate sodium Novartis Australia
Pty Limited PM-2010-01235-3-2 Date of Finalisation 17 May 2013. This Product Information was
approved at the time this AusPAR was published.
7
weeks. A total of 81 patients with biopsy proven lupus nephritis WHO class III, IV, or V and
clinical activity were treated in this study.
The primary efficacy variable was the complete remission rate at 24 weeks defined as the
proportion of patients with urine protein/urine creatinine ratio < 0.5 gram urine protein per
gram urine creatinine, urine sediment normalized (no cellular casts, < 5 red cells per high
power field), and serum creatinine is within 10% of normal value. Secondary efficacy
variables included the proportion patients in partial remission after 24 weeks of treatment,
with partial response defined as a reduction in urine protein:creatinine ratio of ≥50%
compared with base line, and serum creatinine within 10% of baseline value; proportion of
patients with mild SLE flare after 12 and 24 weeks of treatment; disease activity index
measured with BILAG score and SLEDAI index; renal function assessed by serum creatinine,
creatinine clearance, glomerular filtration rate (GFR) and urine protein:creatinine ratio.
The demographic and other baseline characteristics were balanced between the two dose
groups. Most patients had a histological diagnosis of Class IV lupus nephritis. At 6 months,
8/42 (19.0%) of Myfortic and standard corticosteroid-treated patients and 8/39 (20.5%) of
Myfortic and reduced corticosteroid-treated patients achieved complete remission. Partial
response occurred in 20/42 (47.6%) of patients in the standard dose group and 14/39 (35.9%)
of patients in the low dose group. Patients in whom treatment failed included those without
complete or partial remission at 6 months or who prematurely discontinued treatment during
the first 24 weeks for any reason, yielding failure rates of 21/42 (50%) in the standard dose
group and 23/39 (59.0%) in the low dose group. At 6 months, the mean change from
baseline for urine protein to creatinine ratio decreased by 1.1 in the standard dose group and
by 0.8 in the low dose group. Only one patient in the standard-dose group reported a
moderate to mild SLE flare at 24 weeks. The mean BILAG and SLEDI scores decreased
from Week 4 to Week 24 in both treatment groups.
Published studies:
Studies comparing the use of mycophenolate (sodium or mofetil) with intravenous
cyclophosphamide (IVC) and azathioprine (AZA) in patients with proliferative lupus
nephritis have been reported in the literature. Results from the two pivotal published studies
with MMF in induction and maintenance therapy are given below:
The ALMs study (Appel et al., 2009) compared MMF and IVC as induction treatment for
active lupus nephritis in a 24 week open-label parallel group multicentre study. 370 patients
with Class III to V lupus nephritis were randomly assigned to a target dose of 3g/day MMF or
0.5 to 1.0 g/m2 IVC. Both groups received prednisone, tapered from a maximum starting dose
of 60mg/day. The primary endpoint was a pre-specified decrease in urine protein/creatinine
ratio and stabilization or improvement in serum creatinine. Secondary endpoints included
complete renal remission, systemic disease activity and damage, and safety. No significant
difference in response rate between the two groups was detected. The primary efficacy
Attachment 1: Product information for AusPAR Myfortic Mycophenolate sodium Novartis Australia
Pty Limited PM-2010-01235-3-2 Date of Finalisation 17 May 2013. This Product Information was
approved at the time this AusPAR was published.
8
endpoint was achieved in 104 (56.2%) patients receiving MMF, compared with 98 (53.0%)
patients receiving IVC. No significant differences were detected between the MMF and IVC
groups with regard to the rates of adverse events, serious adverse events or infections.
Dooley et al., 2011 conducted a 36 month randomized, double-blind, double dummy study
comparing MMF (2g per day) plus placebo and AZA (2mg per kg per day) plus placebo for
the maintenance of remission in 227 patients who met the response criteria during the ALMS
6-month induction trial with either MMF or IVC. 116 patients were randomly assigned to
MMF and 111 to AZA. The primary endpoint was the time to treatment failure measured as
the time until the first event defined as death, end-stage renal disease, sustained doubling of
the serum creatinine level, renal flare, or the need for rescue therapy. Secondary assessments
included the time to the individual components of treatment failure and adverse events. MMF
was superior to AZA with respect to the primary end point, time to treatment failure (hazard
ratio, 0.44; 95% confidence interval, 0.25 to 0.77; P = 0.003), and with respect to time to
renal flare and time to rescue therapy (hazard ratio, <1.00; P<0.05). Observed rates of
treatment failure were 16.4% (19 of 116 patients) in the MMF group and 32.4% (36 of 111)
in the AZA. Adverse events, most commonly minor infections and gastrointestinal disorders,
occurred in more than 95% of the patients in both groups (P = 0.68). Serious adverse events
occurred in 33.3% of patients in the AZA group and in 23.5% of those in the MMF group (P
= 0.11), and the rate of withdrawal due to adverse events was higher with AZA than with
MMF (39.6% vs. 25.2%, P = 0.02).
Doses used in clinical studies
The doses of mycophenolate sodium (or the equivalent doses when administered as
mycophenolate mofetil) used in the published clinical studies were varied. Doses used for
induction: In the pivotal 24-week ALMS study (Appel et al., 2009) the target dose of MMF
was 3g per day (equivalent of 2.16g mycophenolate sodium or 720mg three times daily). The
median dosage of MMF was calculated as 2.6g/day. In another 24-week published study
(Ginzler et al.,2005), patients were treated with escalating doses of MMF up to 3g per day
(equivalent of 2.16g mycophenolate sodium or 720mg three times daily). In this study the
mean maximum tolerated dose of MMF was 2.68g per day (equivalent to 1.93g
mycophenolate sodium or nearly 720mg three times daily). Doses used for maintenance: In
the pivotal long term maintenance study (Dooley et al., 2011), the target dose of MMF was
2g/day (equivalent to mycophenolate sodium 720mg twice daily); 80% of patients received a
daily dose of 1.6mg or more.
INDICATIONS
- Myfortic is indicated for the prophylaxis of acute transplant rejection in adult patients
receiving allogeneic renal transplants.
- Myfortic is indicated for induction and maintenance treatment of adult patients with WHO
Class III, IV or V lupus nephritis.
Attachment 1: Product information for AusPAR Myfortic Mycophenolate sodium Novartis Australia
Pty Limited PM-2010-01235-3-2 Date of Finalisation 17 May 2013. This Product Information was
approved at the time this AusPAR was published.
9
This indication is based on the evidence in literature reports of studies of treatment in
patients with lupus nephritis, the majority of whom were ISN/RPS (2003) Class IV. The
evidence for efficacy was based on surrogate endpoints.
CONTRAINDICATIONS
Myfortic is contraindicated in pregnancy since it is associated with increased risks of first
trimester pregnancy loss and congenital malformations (see “PRECAUTIONS – Use in
pregnancy”). Females of reproductive potential must be counselled regarding pregnancy
prevention and planning.
It is also contraindicated in patients with a hypersensitivity to mycophenolate sodium,
mycophenolic acid or mycophenolate mofetil or to any of the excipients of the formulation
(see “DESCRIPTION”).
PRECAUTIONS
Embryofoetal toxicity
Myfortic can cause foetal harm when administered to a pregnant woman. Use of Myfortic
during pregnancy is associated with an increased risk of first trimester pregnancy loss and an
increased risk of congenital malformations, especially external ear and other facial
abnormalities including cleft lip and palate, and anomalies of the distal limbs, heart,
esophagus, and kidney.
Women of child-bearing potential
Myfortic therapy should not be initiated until a negative pregnancy test has been
obtained.
Women of child-bearing potential must use highly effective contraception. Two types of
reliable contraception should start before beginning Myfortic therapy, during therapy and for
six weeks after their last dose of Myfortic. Given that mycophenolate mofetil reduces blood
levels of the hormones in the oral contraceptive pill, it is possible that Myfortic could reduce
the efficacy of oral contraceptives (see “PRECAUTIONS, Interactions with other
medicines”).
Pregnancy and breast-feeding, fertility and male patients
For information on use in pregnancy, breast-feeding and contraceptive requirements see
sections entitled “Use in pregnancy”, “Use in lactation”, “Women of child-bearing potential”,
“Effects on fertility” and “Male patients”.
Myfortic should not be used during breast-feeding (see section entitled “Use in lactation”).
Malignancies:
Patients receiving immunosuppressive regimens involving combinations of drugs, including
Myfortic, are at increased risk of developing lymphomas and other malignancies, particularly
Attachment 1: Product information for AusPAR Myfortic Mycophenolate sodium Novartis Australia
Pty Limited PM-2010-01235-3-2 Date of Finalisation 17 May 2013. This Product Information was
approved at the time this AusPAR was published.
10
of the skin (see “ADVERSE EFFECTS”). The risk appears to be related to the intensity and
duration of immunosuppression rather than to the use of any specific agent. In order to
minimise the risk for skin cancer, exposure to sunlight and UV light should be limited by
wearing protective clothing and using a sunscreen with a high protection factor.
Infections:
Patients receiving Myfortic should be instructed to immediately report any evidence of
infection, unexpected bruising, bleeding or any other manifestation of bone marrow
depression.
Oversuppression of the immune system increases the susceptibility to infection, including
opportunistic infections, fatal infections and sepsis (see “ADVERSE EFFECTS”).
Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been
reported in patients treated with MPA derivatives which include mycophenolate mofetil
(MMF) and mycophenolate sodium (see “ADVERSE EFFECTS”). Hemiparesis, apathy,
confusion, cognitive deficiencies and ataxia were the most frequent clinical features observed.
Mycophenolate mofetil is metabolized to mycophenolic acid, the active ingredient in
Myfortic and the active form of the drug. The reported cases generally had risk factors for
PML, including immunosuppressant therapies and impairment of immune functions. In
immunosuppressed patients, physicians should consider PML in the differential diagnosis in
patients reporting neurological symptoms and consultation with a neurologist should be
considered as clinically indicated. Polyomavirus associated nephropathy (PVAN) especially
due to BK virus infection, should be included in the differential diagnosis in
immunosuppressed patients with deteriorating renal function (see “ADVERSE EFFECTS”).
Consideration should be given to reducing the total immunosuppression in patients who
develop PML or PVAN. In transplant patients, however, reduced immunosuppression may
place the graft at risk.
Blood dyscrasias:
Patients receiving Myfortic should be monitored for blood dyscrasias (e.g. neutropenia or
anaemia, see “ADVERSE EFFECTS”), which may be related to MPA itself, concomitant
medications, viral infections or some combination of these causes. Patients takingMyfortic
should have complete blood counts weekly during the first month, twice monthly for the
second and third months of treatment, then monthly through the first year. If blood dyscrasias
occur (e.g. neutropenia with absolute neutrophil count <1.5 x109/L or anaemia), it may be
appropriate to interrupt or discontinue Myfortic.
Cases of pure red cell aplasia (PRCA) have been reported in patients treated with MPA
derivatives in combination with other immunosuppressive agents (see “ADVERSE
EFFECTS”). MMF is metabolised to mycophenolic acid (MPA), the active ingredient in
Myfortic and the active form of the drug. The mechanism for MPA derivatives induced
PRCA is unknown; the relative contribution of other immunosuppressants and their
Attachment 1: Product information for AusPAR Myfortic Mycophenolate sodium Novartis Australia
Pty Limited PM-2010-01235-3-2 Date of Finalisation 17 May 2013. This Product Information was
approved at the time this AusPAR was published.
11
combinations in an immunosuppressive regimen is also unknown. However, MPA derivatives
may cause blood dyscrasias (see above). In some cases PRCA was found to be reversible with
dose reduction or cessation of therapy with MPA derivatives. In transplant patients, however,
reduced immunosuppression may place the graft at risk. Changes to Myfortic therapy should
only be undertaken under appropriate supervision in transplant recipients in order to minimise
the risk of graft rejection.
Vaccinations:
Patients should be advised that, during treatment with MPA, vaccinations may be less
effective and the use of live attenuated vaccines should be avoided (see “PRECAUTIONSInteractions with other medicines”). Influenza vaccination may be of value. Prescribers
should refer to national guidelines for influenza vaccination.
Gastrointestinal disorders:
Because MPA derivatives have been associated with an increased incidence of digestive
system adverse events, including infrequent cases of gastrointestinal tract ulceration and
haemorrhage, and perforation, Myfortic should be administered with caution in patients with
active serious digestive system disease.
Patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT):
Myfortic is an IMPDH (inosine monophosphate dehydrogenase) inhibitor and therefore, on
theoretical grounds, it should be avoided in patients with rare hereditary deficiency of
hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and
Kelley-Seegmiller syndrome.
Male patients
Sexually active men are recommended to use condoms during treatment, and for a total of 13
weeks after their last dose of Myfortic. In addition, female partners of male patients are
recommended to us highly effective contraception during treatment and for a total of 13
weeks after the last dose of Myfortic.
Effects on fertility:
Mycophenolate sodium had no effect on fertility of male rats at oral doses up to
18 mg/kg/day. The systemic exposure to MPA (plasma AUC) at this dose represents
approximately 2 times the clinical exposure at the recommended dose of 1.44 g/day. No
effects on female fertility were seen up to a dose of 20 mg/kg/day, a dose at which
embryotoxicity was observed, with estimated systemic exposure to MPA (plasma AUC)
approximately 3 times clinical exposure.
Attachment 1: Product information for AusPAR Myfortic Mycophenolate sodium Novartis Australia
Pty Limited PM-2010-01235-3-2 Date of Finalisation 17 May 2013. This Product Information was
approved at the time this AusPAR was published.
12
Use in pregnancy (Category D):
Mycophenolate mofetil (MMF) can cause fetal harm when administered to a pregnant
woman. Following oral or IV administration, MMF is metabolized to mycophenolic acid
(MPA), the active ingredient in Myfortic and the active form of the drug. In the US National
Transplantation Pregnancy Registry (NTPR), there were data on 33 MMF-exposed
pregnancies in 24 transplant patients; there were 15 spontaneous abortions (45%) and 18 liveborn infants. Four of these 18 infants had structural malformations (22%). In post-marketing
data (collected from 1995 to 2007) on 77 women exposed to systemic MMF during
pregnancy, 25 had spontaneous abortions and 14 had a malformed infant or fetus. Six of 14
malformed offspring had ear abnormalities. Because these postmarketing data are reported
voluntarily, it is not always possible to reliably estimate the frequency of particular adverse
outcomes. These malformations are similar to findings in animal reproductive toxicology
studies. For comparison, the background rate for congenital anomalies in the United States is
about 3%, and NTPR data show a rate of 4-5% among babies born to organ transplant
patients using other immunosuppressive drugs.
Myfortic should be used in pregnant women only if the potential benefit outweighs the
potential risk to the foetus. Patients should be instructed to consult their physician
immediately should pregnancy occur.
Adverse effects on fetal development (including malformations) occurred when pregnant rats
and rabbits were dosed with mycophenolate sodium or mycophenolate mofetil during
organogenesis. In a teratology study performed with mycophenolate sodium in rats at 1
mg/kg/day (the lowest dose tested), there was an increase in resorptions, and malformations
in the offspring were observed including anophthalmia, exencephaly and umbilical hernia.
The estimated systemic exposure to MPA at this dose is about 0.1 times the clinical exposure
(plasma AUC) at the recommended dose of 1.44 g/day.
Use in lactation:
It is not known whether MPA is excreted in human milk but studies in rats given
radiolabelled mycophenolate mofetil have shown the excretion of radioactivity into milk.
Myfortic should not be used during lactation.
Because many drugs are excreted in human milk and of the potential for serious adverse
reactions in breastfed newborns/infants, a decision should be made whether to abstain from
breast-feeding while on treatment and during 6 weeks after stopping the therapy or to abstain
from using the medicinal product taking into account the importance of the drug to the
mother.
Paediatric use:
Safety and efficacy in paediatric patients have not been established.
Attachment 1: Product information for AusPAR Myfortic Mycophenolate sodium Novartis Australia
Pty Limited PM-2010-01235-3-2 Date of Finalisation 17 May 2013. This Product Information was
approved at the time this AusPAR was published.
13
Genotoxicity:
Mycophenolate sodium and mycophenolate mofetil were genotoxic in the mouse
lymphoma/thymidine kinase assay, the micronucleus test in V79 Chinese hamster cells in
vitro and in the in vivo mouse micronucleus assay. They were not genotoxic in the bacterial
mutation assay. Mycophenolate sodium showed weak evidence of genotoxicity in the
chromosome aberration assay in human lymphocytes. There were no relevant qualitative or
quantitative differences in the genotoxic potential of mycophenolate sodium and
mycophenolate mofetil. The genotoxic activity of MPA may be due to a shift in the relative
abundance of the nucleotides in the cellular pool used for DNA synthesis.
Carcinogenicity:
In a 104-week oral carcinogenicity study in rats, mycophenolate sodium at daily doses up to
9 mg/kg was not tumorigenic. The highest dose tested resulted in approximately 0.6-1.2
times the systemic exposure observed in renal transplant patients at the recommended dose of
1.44 g/day. Similar results were observed in a parallel study in rats performed with
mycophenolate mofetil. In a 26-week oral carcinogenicity assay in a P53 (heterozygous)
transgenic mouse model, mycophenolate sodium at daily doses up to 200 mg/kg was not
tumorigenic. The highest dose tested resulted in approximately 5 times the systemic exposure
(plasma AUC) observed in renal transplant patients taking 1.44 g/day. The results of this
study, however, remain equivocal because of the lack of a response to the positive control
compound, benzene.
In a 2-year carcinogenicity study in rats, administration of oral doses of 6 and 9 mg/kg/day
mycophenolate sodium resulted in an increase in the incidence of benign thymomas in the
thymus in females. Systemic exposure (plasma AUC) at these respective doses was about 0.5
and 1 times that observed in renal transplant patients taking 1.44 g/day.
Effects on ability to drive and use machinery:
No studies on the effects of Myfortic on the ability to drive and use machines have been
performed. The mechanism of action and pharmacodynamic profile and the reported adverse
reactions indicate that an effect is unlikely.
INTERACTIONS WITH OTHER MEDICINES
Myfortic has been administered in combination with the following agents in clinical trials:
antithymocyte globulin, basiliximab, cyclosporin and corticosteroids. The efficacy and safety
of the use of Myfortic with other immunosuppressive agents have not been studied.
Oral contraceptives: Concomitant use of Myfortic with oral contraceptives has not been
studied. Oral contraceptives undergo oxidative metabolism while Myfortic is metabolised by
glucuronidation. Given the different metabolism of Myfortic and oral contraceptives, no drug
interaction between these two classes of drug is expected. However, in a drug-drug
interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered
Attachment 1: Product information for AusPAR Myfortic Mycophenolate sodium Novartis Australia
Pty Limited PM-2010-01235-3-2 Date of Finalisation 17 May 2013. This Product Information was
approved at the time this AusPAR was published.
14
with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are
coadministered with Myfortic with caution and additional birth control methods be
considered (see PRECAUTIONS Section – “Women of child-bearing potential” and “Male
patients”).
Azathioprine: It is recommended that Myfortic should not be administered concomitantly
with azathioprine because such concomitant administration has not been studied.
Live vaccines: Live vaccines should not be given to patients with an impaired immune
response. The antibody response to other vaccines may be diminished.
Aciclovir: Concomitant use of Myfortic with aciclovir has not been studied. After coadministration of mycophenolate mofetil (which delivers MPA to the systemic circulation)
and aciclovir, higher plasma concentrations of MPAG and aciclovir have been observed
compared with administration of each drug alone. In renal impairment, the two drugs may
compete for tubular secretion resulting in further increases in MPAG and aciclovir plasma
concentration. In this situation, patients should be carefully monitored.
Cyclosporin: When studied in stable renal transplant patients, cyclosporin (Neoral)
pharmacokinetics were unaffected by steady state dosing of Myfortic.
Ganciclovir: Concomitant use of Myfortic with ganciclovir has not been studied. In patients
taking mycophenolate mofetil, MPA and MPAG pharmacokinetics are unaffected by the
addition of ganciclovir. The clearance of ganciclovir is unchanged in the setting of
therapeutic MPA exposure. However, in patients with renal impairment in whom Myfortic
and ganciclovir are coadministered, the potential exists for the two drugs to compete for
tubular secretion, resulting in increased plasma concentrations of both drugs. Therefore, in
patients with renal impairment, the dose recommendations for ganciclovir should be observed
and patients carefully monitored.
Tacrolimus: In a calcineurin cross-over study in stable renal transplant patients, steady state
Myfortic pharmacokinetics were determined during concomitant cyclosporin (Neoral) and
tacrolimus (Prograf®) treatments. Mean MPA AUC was 19% higher and Cmax about 20%
lower, and mean MPAG AUC and Cmax were about 30% lower on tacrolimus treatment
compared to Neoral treatment.
Conditions of decreased protein binding sites: MPA concentration may increase under
conditions of decreased protein binding sites, which may occur when Myfortic is
administered concomitantly with highly protein bound drugs and/or in the setting of uraemia.
This may put patients at increased risk of MPA-related adverse effects.
Attachment 1: Product information for AusPAR Myfortic Mycophenolate sodium Novartis Australia
Pty Limited PM-2010-01235-3-2 Date of Finalisation 17 May 2013. This Product Information was
approved at the time this AusPAR was published.
15
Gastroprotective agents:
Antacids with magnesium and aluminium hydroxides: The absorption of Myfortic was
decreased when administered with antacids containing magnesium and aluminium hydroxide,
resulting in a 37% decrease in MPA systemic exposure and a 25% decrease in MPA maximal
concentration. Caution should be used when co-administering antacids containing
magnesium and aluminium hydroxide with Myfortic.
Proton Pump inhibitors: In healthy volunteers, no changes in the pharmacokinetics of MPA
were observed following concomitant administration of Myfortic and pantoprazole given at 40
mg twice daily during the four previous days.
Cholestyramine and drugs that interfere with enterohepatic circulation: Due to its capacity to
block the enteric circulation of drugs, cholestyramine may decrease the systemic exposure of
MPA. Caution should be used when co-administering cholestyramine or drugs that interfere
with enterohepatic circulation because of the potential to reduce the efficacy of Myfortic.
ADVERSE EFFECTS
Adverse effects from clinical trials in renal transplant patients
Malignancies:
Patients receiving immunosuppressive regimens involving combinations of drugs, including
MPA, are at increased risk of developing lymphomas and other malignancies, particularly of
the skin (see “PRECAUTIONS-Development of malignancies”). Overall rates of
malignancies observed in Myfortic clinical trials are as follows: lymphoproliferative disease
or lymphoma developed in 2 de novo patients (0.9%) and in 2 maintenance patients (1.3%)
receiving Myfortic for up to 1 year; non-melanoma skin carcinomas occurred in 2 de novo
patients (0.9%) and 3 maintenance patients (1.9%) receiving Myfortic for up to 1 year; other
types of malignancy occurred in 0.5% of de novo and 0.6% of maintenance patients.
Opportunistic infections:
All transplant patients are at increased risk of opportunistic infections. The risk increases with
total immunosuppressive load (see “PRECAUTIONS-Development of infections”). The
most common opportunistic infections in de novo renal transplant patients receiving Myfortic
with other immunosuppressants in controlled clinical trials of renal transplant patients
followed for one year were CMV, candidiasis and herpes simplex. The overall rate of CMV
infections (serology, viraemia or disease) observed in Myfortic clinical trials was 21.6% in de
novo and 1.9% in maintenance renal transplant patients.
Other adverse drug reactions:
Table 4 below contains adverse drug reactions, possibly or probably related to Myfortic,
reported in the two phase III randomised, double blind, controlled, multi-centre trials: 1 in de
novo renal transplant patients and 1 in maintenance renal transplant patients, in which
Myfortic was administered at a dose of 1440 mg /day for 12 months together with cyclosporin
Attachment 1: Product information for AusPAR Myfortic Mycophenolate sodium Novartis Australia
Pty Limited PM-2010-01235-3-2 Date of Finalisation 17 May 2013. This Product Information was
approved at the time this AusPAR was published.
16
microemulsion (Neoral) and corticosteroids. It is compiled according to MedDRA system
organ class.
Adverse reactions are listed according to the following categories:
Very common ≥ 10 % (≥ 1/10)
Common
≥ 1 % and < 10 % (≥ 1/100 and < 1/10)
Uncommon
≥ 0.1 % and < 1 % (≥ 1/1000 and < 1/100)
Rare
≥ 0.01% and < 0.1 % (≥ 1/10000 and < 1/1000)
Very rare
< 0.01 % (< 1/10000)
Table 4
Body system
Infections and infestations
Incidence
Very common
Common
Blood and lymphatic system
disorders
Nervous system disorders
Respiratory, thoracic and
mediastinal disorders
Gastrointestinal disorders
Uncommon
Very common
Common
Uncommon
Common
Uncommon
Common
Uncommon
Very common
Common
Uncommon
General disorders and
administration site conditions
Common
Uncommon
Metabolism and nutrition disorders
Uncommon
Skin and cutaneous tissue disorders
Hepato-biliary disorders
Cardiac disorders
Uncommon
Common
Uncommon
Eye disorders
Uncommon
Adverse reaction
Viral, bacterial and fungal infections
Upper respiratory tract infections,
pneumonia
Wound infection*, sepsis*,
osteomyelitis*
Leukopenia
Anaemia, thrombocytopenia
Lymphocele*, lymphopenia*,
neutropenia*, lymphadenopathy*
Headache
Tremor, insomnia*
Cough
Pulmonary congestion, wheezing
Diarrhoea
Abdominal distension, abdominal
pain, abdominal tenderness,
constipation, dyspepsia, flatulence,
gastritis, loose stools, nausea,
vomiting
Pancreatitis, eructation, halitosis,
ileus, oesophagitis*, peptic ulcer*,
subileus*, tongue discolouration*,
gastrointestinal haemorrhage, dry
mouth, lip ulceration, parotid duct
obstruction*, gastro-oesophageal
reflux disease, gingival hyperplasia,
peritonitis*
Fatigue, pyrexia
Influenza like illness, oedema lower
limb*, pain, rigors*, thirst* weakness*
Anorexia, hyperlipidaemia, diabetes
mellitus*, hypercholesterolaemia,
hypophosphataemia*
Alopecia, contusion*
Abnormal hepatic function tests
Tachycardia, pulmonary oedema*,
ventricular extrasystoles*
Conjunctivitis*, blurred vision*
Attachment 1: Product information for AusPAR Myfortic Mycophenolate sodium Novartis Australia
Pty Limited PM-2010-01235-3-2 Date of Finalisation 17 May 2013. This Product Information was
approved at the time this AusPAR was published.
17
Musculoskeletal, connective tissue
and bone disorders
Neoplasms benign and malignant
Uncommon
Arthritis*, back pain*, muscle cramps
Uncommon
Psychiatric disorders
Uncommon
Renal and urinary disorders
Common
Uncommon
Reproductive system and breast
disorders
Uncommon
Skin papilloma*, basal cell
carcinoma*, Kaposi’s sarcoma*,
lymphoproliferative disorder,
squamous cell carcinoma*
Abnormal dreams*, delusional
perception*
Increased blood creatinine
Hematuria*, renal tubular necrosis*,
urethral stricture
Impotence*
* Events reported in a single patient only.
Renal transplant patients were treated with 1440 mg Myfortic daily up to one year. A similar
profile was seen in the de novo and maintenance transplant population although the incidence
tended to be lower in the maintenance patients.
Elderly patients:
Elderly patients may generally be at increased risk of adverse drug reactions due to
immunosuppression. Elderly patients receiving Myfortic as part of a combination
immunosuppressive regimen did not show an increased risk of adverse reactions compared to
younger individuals in the Myfortic clinical trials.
Adverse effects from a clinical trial in lupus nephritis patients (A2420)
Myfortic was administered at a dose of 720 mg twice daily for 2 weeks and then 1080 mg
twice daily (or 720 mg three times daily) for 22 weeks in an open-label trial comparing the
efficacy and safety of Myfortic and a standard corticosteroid regimen (prednisolone 1 mg/kg
bodyweight/day, tapered) with Myfortic and a reduced corticosteroid regimen (prednisolone
0.5 mg/kg bodyweight/day, tapered) for induction treatment of lupus nephritis. Adverse
events were reported by 35/42 (83.3%) patients in the Myfortic and standard corticosteroid
group and by 30/39 (76.9%) patients in the Myfortic and reduced corticosteroid group. The
incidence of gastrointestinal events (standard: 18/42, 42.9%; reduced: 13/39, 33.3%),
infections (standard: 25/42, 59.5%; reduced: 14/39, 35.9%), and general disorders (standard:
14/42, 33.3%; reduced: 8/39, 20.5%) were higher in the Myfortic and standard corticosteroid
group compared with the Myfortic and reduced corticosteroid group.
Adverse effects from post marketing experience
Rash has been identified as an adverse effect from post-approval clinical trials, post
marketing surveillance and spontaneous reports.
The following additional adverse reactions are attributed to MPA derivatives as a class effect:
Congenital malformations have been reported in offspring of patients exposed to
mycophenolate mofetil (MMF) during pregnancy (see PRECAUTIONS, Use in pregnancy).
Attachment 1: Product information for AusPAR Myfortic Mycophenolate sodium Novartis Australia
Pty Limited PM-2010-01235-3-2 Date of Finalisation 17 May 2013. This Product Information was
approved at the time this AusPAR was published.
18
Infections and Infestations: serious, sometimes life-threatening infections, including
meningitis, infectious endocarditis, tuberculosis and atypical mycobacterial infection.
Polyomavirus associated nephropathy (PVAN), especially due to BK virus infection.Cases of
progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported (see
“PRECAUTIONS”).
Blood and lymphatic system disorders: neutropenia, pancytopenia. Cases of pure red cell
aplasia (PRCA) have been reported in patients treated with MPA derivatives in combination
with other immunosuppressive agents (see “PRECAUTIONS”).
Gastrointestinal disorders: colitis, oesophagitis (including CMV-colitis and -oesophagitis),
CMV gastritis, pancreatitis, intestinal perforation, gastrointestinal haemorrhage, gastric
ulcers, duodenal ulcers, ileus.
DOSAGE AND ADMINISTRATION
Treatment with Myfortic should be initiated and maintained by appropriately qualified
specialists who are expert in managing the safety risks associated with the contraindication
for use in pregnancy. Consideration should be given to therapeutic drug monitoring of
mycophenolate because of the variable pharmacokinetic profile and narrow therapeutic
margin.
Myfortic should not be initiated in women of child-bearing potential until a negative
pregnancy test has been obtained. For information on use in pregnancy and contraceptive
requirements see sections entitled “Women of child-bearing potential”, “Use in pregnancy”,
and “Male patients”).
A dose of 1440mg/day of mycophenolate sodium has been shown to be equivalent to 2 g/day
of mycophenolate mofetil. Myfortic and CellCept (mycophenolate mofetil) should not be
indiscriminately interchanged or substituted because of their different pharmacokinetic
profiles.
Myfortic tablets should not be crushed and should be swallowed whole. Patients should be
advised to take Myfortic consistently either with or without food, but not switch between fed
and fasted states because of the risk of increased MPA AUC variability.
Renal transplant patients:
Myfortic should be initiated in de novo patients within 48 hours following transplantation.
The recommended dose is 720 mg administered twice daily (1440 mg daily dose).
Paediatric patients:
Safety and efficacy in paediatric patients have not been established
Attachment 1: Product information for AusPAR Myfortic Mycophenolate sodium Novartis Australia
Pty Limited PM-2010-01235-3-2 Date of Finalisation 17 May 2013. This Product Information was
approved at the time this AusPAR was published.
19
Elderly patients:
No dose adjustment is required in elderly patients.
Patients with renal insufficiency:
No dose adjustments are needed in patients experiencing delayed renal graft function postoperatively. Patients with severe chronic renal impairment (glomerular filtration rate < 25
ml·min-1·1.73 m-2) should be carefully monitored.
Patients with hepatic insufficiency:
No dose adjustments are needed for renal transplant patients with severe hepatic parenchymal
disease.
Treatment during rejection episodes:
Dosage reduction or interruption of Myfortic is not required during episodes of renal
transplant rejection.
Lupus nephritis patients:
Adequate dose finding studies have not been performed. The prescriber should adjust the
dose based on clinical response.
Induction treatment with Myfortic is usually initially administered in combination with
corticosteroids. The recommended dose is 720mg administered twice daily (1440mg daily
dose). A daily dose of greater than 1440mg/day has been used for induction therapy in some
studies (see ‘Clinical Trials” section). This dose may be tapered for maintenance purposes
following a complete or partial response.
OVERDOSAGE
Signs and symptoms:
There has been no reported experience of overdosage of Myfortic in humans.
Treatment:
Although dialysis may be used to remove the inactive metabolite MPAG, it would not be
expected to remove clinically significant amounts of the active moiety, MPA. This is in large
part due to the very high plasma protein binding of MPA. By interfering with enterohepatic
circulation of MPA, bile acid sequestrants such as cholestyramine may reduce the systemic
exposure of MPA.
Contact Poison Information Centre on 13 11 26 for advice on management.
PRESENTATION AND STORAGE CONDITIONS
Presentation:
Myfortic 180 mg:
Lime green, enteric-coated, round tablet with bevelled edges and the imprint “C” on one side.
Attachment 1: Product information for AusPAR Myfortic Mycophenolate sodium Novartis Australia
Pty Limited PM-2010-01235-3-2 Date of Finalisation 17 May 2013. This Product Information was
approved at the time this AusPAR was published.
20
Myfortic 360 mg:
Pale orange red, enteric-coated, ovaloid tablet with imprint ‘CT’ on one side.
Packs containing 50 or 120 tablets.
Storage conditions:
Store in original package and container below 30C. Protect from moisture and light. Keep
out of reach of children.
NAME AND ADDRESS OF THE SPONSOR
NOVARTIS Pharmaceuticals Australia Pty Limited
ABN 18 004 244 160
54 Waterloo Road
North Ryde NSW 2113
® = Registered Trademark
POISON SCHEDULE OF THE MEDICINE
Schedule 4
DATE OF FIRST INCLUSION IN THE AUSTRALIAN REGISTER
OF THERAPEUTIC GOODS (ARTG)
25 March 2003 (180mg tablet); 26 March 2003 (360mg tablet)
DATE OF MOST RECENT AMENDMENT
7 September 2012
____________________________________________________________
For internal use only:
(myf030912i) based on CDS 18 July 2011.